RESUMEN
A potent IRAK-4 inhibitor was identified through routine project cross screening. The binding mode was inferred using a combination of in silico docking into an IRAK-4 homology model, surrogate crystal structure analysis and chemical analogue SAR.
Asunto(s)
Diseño de Fármacos , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/farmacología , Imidazoles/síntesis química , Imidazoles/farmacología , Quinasas Asociadas a Receptores de Interleucina-1/antagonistas & inhibidores , Modelos Moleculares , Piridinas/síntesis química , Piridinas/farmacología , Sitios de Unión , Cristalografía por Rayos X , Inhibidores Enzimáticos/química , Imidazoles/química , Conformación Molecular , Estructura Molecular , Piridinas/química , Relación Estructura-ActividadRESUMEN
The synthesis and profile of a series of amides are described. Some of these compounds were potent IRAK-4 inhibitors and two examples were evaluated in vivo.
Asunto(s)
Amidas/síntesis química , Amidas/farmacología , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/farmacología , Quinasas Asociadas a Receptores de Interleucina-1/antagonistas & inhibidores , Modelos Biológicos , Piridinas/síntesis química , Piridinas/farmacología , Bibliotecas de Moléculas Pequeñas/síntesis química , Bibliotecas de Moléculas Pequeñas/farmacología , Amidas/química , Diseño de Fármacos , Inhibidores Enzimáticos/química , Humanos , Estructura Molecular , Piridinas/química , Bibliotecas de Moléculas Pequeñas/química , Relación Estructura-ActividadRESUMEN
Here we review the use of informatics in structural interactomics, with particular emphasis on understanding interfacial contacts in the development of novel therapeutics and the interpretation of genetic variation. We describe the availability and applicability of structural databases of protein interactions which facilitate this endeavour. We demonstrate the applicability of a structural interactomics approach to the study of the fibroblast growth factor (FGF)-stimulated mitogen-activated protein kinase (MAPK) pathway.
Asunto(s)
Biología Computacional , Bases de Datos Genéticas , Descubrimiento de Drogas , Variación Genética , Humanos , Mapeo de Interacción de Proteínas , Transducción de SeñalRESUMEN
In this paper we have investigated at the DFT(B3LYP) level the catalytic cycle for the bis-silylation reaction of alkynes promoted by palladium complexes. A model-system formed by an acetylene molecule, a disilane molecule, and the Pd(PH(3))(2) complex has been used. The most relevant features of this catalytic cycle can be summarized as follows: (i) The first step of the cycle is an oxidative addition involving H(3)Si-SiH(3) and Pd(PH(3))(2). It occurs easily and leads to the cis (SiH(3))(2)Pd(PH(3))(2) complex that is 5.39 kcal mol(-1) lower in energy than reactants. (ii) The transfer of the two silyl groups to the C-C triple bond does not occur in a concerted way, but involves many steps. (iii) The cis (SiH(3))(2)Pd(PH(3))(2) complex, obtained from the oxidative addition, is involved in the formation of the first C-Si bond (activation barrier of 18.34 kcal mol(-1)). The two intermediates that form in this step cannot lead directly to the formation of the final bis(silyl)ethene product. However, they can isomerize rather easily (the two possible isomerizations have a barrier of 16.79 and 7.17 kcal mol(-1)) to new more stable species. In both these new intermediates the second silyl group is adjacent to the acetylene moiety and the formation of the second C-Si bond can occur rapidly leading to the (Z)-bis(silyl)ethene, as experimentally observed. (iv) The whole catalytic process is exothermic by 41.54 kcal mol(-1), in quite good agreement with the experimental estimate of this quantity (about 40 kcal mol(-1)).